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Transthyretin orchestrates vitamin B12-induced stress resilience [II]

ABSTRACT: Background: Chronic stress significantly contributes to mood- and anxiety disorders. Previous data suggest a correlative connection between vitamin B12 supplementation, depression, and stress resilience. However, the underlying mechanisms are still poorly understood. Methods: Using the chronic variable stress mouse model coupled with RNA-sequencing, we determined vitamin B12-induced transcriptional changes related to stress resilience. By viral-mediated gene transfer and in vivo epigenome editing, we reveal a functional pathway linking vitamin B12, DNA methylation, and depressive-like symptoms. Results: We identified Transthyretin (Ttr) as a sex-specific key target of vitamin B12 action in chronic stress. Accordingly, TTR expression was increased postmortem in the prefrontal cortex of male, but not female, depressed patients. Virally altered Ttr in the prefrontal cortex functionally contributed to stress- and depression-related behaviors, changes in dendritic spine morphology, and gene expression. In stressed mice, vitamin B12 reduced DNAme in the Ttr promoter region. Importantly, using in vivo epigenome editing to alter DNAme in the brains of living mice for the first time, we establish a direct causal link between DNAme on Ttr and stress-associated behaviors. Discussion: In summary, using state-of-the-art techniques, this study uncovers a mechanistic link between cobalamin supplementation, Ttr, and markers of chronic stress and depression, encouraging further studies into dietary interventions for mood disorders.

ORGANISM(S): Mus musculus

PROVIDER: GSE267339 | GEO | 2024/05/18

REPOSITORIES: GEO

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Project description:Background: Examining transcriptional regulation by existing antidepressants in key neural circuits implicated in depression, and understanding the relationship to transcriptional mechanisms of susceptibility and natural resilience, may help in the search for new therapeutics. Further, given the heterogeneity of treatment response in human populations, examining both treatment response and non-response is critical. Methods: We compared the effects of a conventional monoamine-based tricyclic antidepressant, imipramine (14 daily injections), and a rapidly acting, experimental, non-monoamine-based antidepressant, ketamine (single injection), in mice subjected to chronic social defeat stress, a validated model of depression, and used RNA-sequencing to analyze transcriptional profiles associated with susceptibility, resilience and antidepressant response and non-response in prefrontal cortex (PFC), nucleus accumbens, hippocampus, and amygdala. Results: We identified approximately equal numbers of responder and non-responder mice following ketamine or imipramine treatment. Ketamine induced more expression changes in hippocampus than other brain regions; imipramine induced more expression changes in nucleus accumbens and amygdala. Transcriptional profiles in ketamine and imipramine responders were most similar in PFC, where the least transcriptional regulation occurred for each drug. Non-response reflected both the lack of response-associated gene expression changes and unique gene regulation. In responders, both drugs reversed susceptible associated transcriptional changes as well as induced resilient associated transcription in PFC, with effects varying by drug and brain region studied. Conclusions: We generated a uniquely large resource of gene expression data in four inter-connected limbic brain regions implicated in depression and its treatment with imipramine or ketamine. Our analyses highlight the PFC as a key site of common transcriptional regulation by both antidepressant drugs and in both reversing susceptibility and inducing resilience associated molecular adaptations. In addition, we found region-specific effects of each drug suggesting both common and unique effects of imipramine versus ketamine. mRNA profiles of susceptibility to chronic social defeat stress as well as treatment response were generated across 4 separate brain regions, with a sample size of 3-5 per group.

Project description:Background: Selective serotonin reuptake inhibitors (SSRIs), used to treat prenatal maternal depression, have been associated with neurobehavioral disturbances in exposed neonates, though the underlying molecular mechanisms remain poorly understood. In utero exposure to SSRIs may have an effect on DNA methylation (DNAme) in the human placenta, which is an epigenetic mark that is established during development and is associated with gene expression. Methods: Chorionic villus samples from 64 human placentas were profiled with the Illumina MethylationEPIC BeadChip and clinical assessments of maternal mood were collected at multiple time points during pregnancy. Case distribution was 20 SSRI-exposed cases and 44 SSRI non-exposed cases. Maternal depression using a mean maternal Hamilton Depression score >8 to indicate symptomatic depressed mood (“maternally-depressed”) further classified cases into SSRI-exposed, maternally-depressed (n=14); SSRI-exposed, not maternally-depressed (n=6); SSRI non-exposed, maternally-depressed (n=20); and SSRI non-exposed, not maternally-depressed (n=24). To provide a replication cohort, Illumina 450K DNAme profiles were obtained from 34 additional cases from an independent cohort (n=17 SSRI-exposed, n=17 SSRI non-exposed). Results: No CpGs were differentially methylated at FDR < 0.05 comparing SSRI-exposed to non-exposed placentas, while adjusting for mean maternal Hamilton Depression score, nor comparing SSRI-exposed maternally-depressed to SSRI-non-exposed maternally-depressed cases. At a relaxed threshold of FDR < 0.25, five CpGs were differentially methylated (|Δβ| > 0.03) by SSRI exposure status. Four of these CpGs were covered by the 450K array and were examined in the replication cohort, but none replicated. Amongst SSRI non-exposed cases, No CpGs were differentially methylated (FDR < 0.25) comparing maternally depressed to not depressed cases. In sex-stratified analyses for SSRI-exposed versus non-exposed cases (females n=31; males n=33), three additional CpGs in females, but none in males, were differentially methylated at the relaxed FDR < 0.25 cut-off. Conclusions: We did not observe large-scale alterations of DNAme in placentas exposed to maternal SSRI treatment compared to placentas with no SSRI exposure. We also found no evidence for altered DNAme in maternal depression-exposed versus depression non-exposed placentas. This novel work in a prospectively-recruited cohort with clinician-ascertained SSRI exposure and mood assessments would benefit from future replication.

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Transthyretin orchestrates vitamin B12-induced stress resilience [II]

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